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Malaria parasites can hide in people’s bodies for years or even decades without causing symptoms by shutting down the genes that make them visible to the immune system, a new report found.

This discovery explains how people can remain infected years after developing malaria and spread the disease through mosquitos that bite them, said Kirk W. Deitsch, PhD, professor with the Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York City, and co-author of a study published in Nature Microbiology.

“What’s probably happening in a place like Africa, where there’s a lot of malaria transmission, is that people we thought didn’t have malaria actually had these invisible parasites at really low levels in their system,” Deitsch told Medscape Medical News.

The implications for elimination campaigns are significant. Currently, “when we try to do a malaria elimination campaign, [we] treat the kids, the ones who are sick,” he said. The study suggests “that we need to treat all asymptomatic people, the adults, because they’re carrying these cryptic parasites that nobody knew about before.”

Sticky Proteins and Spleen Avoidance

The researchers sought to better understand how malaria persists in the body.

“There were these weird cases where a person who grew up in, let’s say, Africa, had malaria several times, were no longer infected, and moved to the States. They lived in the States for a decade, maybe 12 or 13 years, and then they give blood for a transfusion, and the recipient of the transfusion gets really bad malaria,” Deitsch said.

“So clearly, those parasites have been hiding in this person for more than a decade, and nobody knew why. How are they hiding? Where are they?”

Study authors focused on the var gene, which expresses an adhesive surface protein on the infected red blood cells in malaria. The protein is “sticky,” allowing infected cells to attach to blood vessel walls and avoid being filtered out by the spleen, Deitsch said. But the parasite pays a price because the immune system can detect the sticky protein.

Previous methods of analyzing the genetics of malaria looked at millions of parasites together. “If you want to know which gene is being turned on in that population, you take all those parasites, you extract all the RNA from the population, and you look at which gene is turned on,” Deitsch explained.

For the new study, researchers analyzed the malaria parasite at the single-cell level. “We isolated single parasites and then looked at which gene is being expressed by just that individual parasite,” he said. “We found there was always a group of parasites that had turned off the entire [var] gene family and were expressing no genes at all.” 

As a result, the red blood cells didn’t produce the surface proteins, allowing them to be “invisible” and evade the immune system.

Like a Criminal

The parasites don’t turn invisible right away, Deitsch said. Instead, they constantly switch to different sticky proteins, like a criminal changing disguises, as the immune system swings into action. “As soon as your antibody titer begins to rise, they just switch to a different adhesive protein.”

“The parasite only has so many copies of this adhesive protein that they can put out to the surface over their lifetime. So they run out of genes after about a year and a half or so.”

Scientists used to think this meant the infection would be cleared. “Everybody always assumed that once the parasite runs out of these genes, that the infection is over. You clear the infection, and then you’re okay.”

Deitsch used the metaphor of a criminal who has a closet full of 50-60 disguises. “When you get to the last one, then you’ve run out, and the cops have figured out all your previous disguises. At the back of the closet, there’s an invisibility cloak. They can put that on, and then the cops can’t see you at all.”

These invisible parasites exist at very low levels. “Those parasites don’t go to very high levels because your spleen is continuously filtering them,” Deitsch explained. “But what they’re able to do is maintain this low level of infection for a long time.”

The only sign of continued infection may be a slightly enlarged spleen “because the spleen is continuously clearing a lot of these invisible parasites by filtration,” Deitsch noted.

Changes in Malaria Prevention Strategy?

The findings suggest that anti-malaria efforts should treat entire populations with anti-malaria drugs, even healthy people, Deitsch said. And drugs could be developed to make the hidden parasites become visible to the immune system.

However, neither strategy is simple, he said.

What’s next? “We’re going to continue working on the molecular mechanisms that mediate this process [and explore] how the parasites control their chromosomes and their genes to go into this silent, invisible state and then switch back out into a different state,” Deitsch said.

Researchers are also studying basic questions about how parasites coordinate their disguise changes. “There are literally trillions of parasites in the circulation of a sick individual, and they seem to coordinate switching their disguise,” Deitsch said. “They all know to go to the same next disguise.”

Outside Experts Weigh In

Karine Le Roch, PhD, MS, director of the Center for Infectious Disease and Vector Research, University of California, Riverside, who was not involved with the paper, told Medscape Medical News that it’s “a rigorous, innovative, and impactful study that advances a long-standing question in malaria biology.”

The report “addresses a major paradox in malaria biology and offers a compelling explanation for asymptomatic chronic infections, which have long been poorly understood,” she said.

Anna Bachmann, PhD, a research group leader at the Bernhard Nocht Institute for Tropical Medicine in Hamburg, Germany, also praised the study.

Bachmann, who didn’t work on the paper, said it suggests “that P falciparum may possess even more sophisticated strategies to maintain long-term infections than previously understood.”

She added that the findings have implications regarding whether migrants need more extensive screening and treatment for acute and chronic infections.

“Many parasitic infections in refugees from sub-Saharan Africa have been found to be clinically almost silent, leading to the recommendation that screening practices need to be improved, particularly with respect to parasitic infections,” she said. “This is primarily to improve the health of migrants, but it could also become relevant in the context of a potential reintroduction of malaria in nonendemic regions as currently being observed in parts of the United States and southern Europe.”

The National Institutes of Health supported Deitsch and another author via grants. Deitsch is a Stavros S. Niarchos Scholar and recipient of a William Randolph Hearst Endowed Faculty Fellowship Grant, and the William Randolph Hearst Foundation supported his institution. Another author received support from the Swiss National Science Foundation. The other authors had no disclosures.

Le Roch, who has worked with Deitsch, and Bachmann had no disclosures.